Global Association of Cause-specific Mortality between the Major Gastrointestinal Cancers and Parkinson’s Disease for the First Two Decades of the New Millennium

Parkinson’s disease (PD) and gastrointestinal (GI) cancers are both “age-related diseases” sharing several environmental risk factors, but possess opposite underlying biological mechanisms. Aim of this study was to evaluate the correlations between GI cancers and PD using national cause-specific mortality data of 183 countries extracted from the Global Health Observatory database. The association between PD- and GI cancers- (i.e. esophagus cancer, EC; stomach cancer, SC; colorectal cancer, CRC; liver cancer, LC and pancreatic cancer, PC) specific mortality on the country level was evaluated using Spearman correlation and logistic regression analysis. A global increase in mortality from 2000 to 2019 was observed in PD, CRC and PC, whereas in EC, SC and LC it decreased. We see the consistent diminishment of correlation intensities between PD and GI cancer mortalities from 2000 to 2019 as a positive development. In 2019, PD inversely correlated with CRC (rs = -0.39) and PC (rs = -0.40, all P < 0.001) but not with EC and SC. Of note, an exceptionally positive correlation of PD with LC (rs = 0.26, P < 0.001) and its two hepatitis B and C virus-associated subtypes was revealed. Logistic regression analysis further determined that PD associated negatively with CRC (OR = 0.25) and PC (OR = 0.21, both P < 0.001), but positively with LC (OR = 2.27, P = 0.007). Consequently, future research aiming to unravel the functional biological link between neurodegeneration, hepatitis and tumor development holds great potential for developing novel therapeutics.


METHODS
The global crude death rate was calculated as follows: death number / total population and is presented as rate per 100,000 inhabitants. The national mortality is given as age-standard mortality per 100,000 inhabitants [10][11][12]. We included the main GI cancers: EC, SC, CRC, LC and PC. Moreover, the three subgroups of LC (LC secondary to hepatitis B (LC_hB), to hepatitis C (LC_hC) and to alcohol abuse (LC_alcohol)) were investigated separately.
The analysis variables included year of estimate (2000, 2010 and 2019) and gender (male and female). The correlation between PD-and GI cancers-specific mortality was evaluated using Spearman correlation analysis and is presented by correlation coefficient, r s and 95% confidence intervals (CIs). In order to define the risk factors, all countries were divided into two groups (highversus low-mortality countries) based on the median value of PD-and GI cancers-specific mortality (cutoff value of EC: 2.45; SC: 6.00; CRC: 8.70; LC: 5.40; LC_hB: 1.40; LC_hC: 1.50; LC_alcohol: 1.40; PC: 3.70 and PD: 4.10 per 100,000); then evaluated the impact of PD on the higher mortality of GI cancers at a national level using logistic regression analysis and shown as odds ratios (ORs) and 95% CIs. Statistical analyses were performed by IBM SPSS Statistics, version 20.0, and P < 0.05 was considered statistically significant.

RESULTS
For the year 2019, 328,645 deaths from PD, 462,995 deaths for EC, 830,682 for SC, 916,166 for CRC, 577,430 for LC and 447,208 for PC were reported globally, with males always being more frequently affected than females (Fig. 1A). For LC, 38.29% and 19.87% deaths are secondary to hepatitis B and alcohol, respectively. Whereas 29.39% LC deaths are secondary to hepatitis C and solely in this pathology, females are more often affected (Fig. 1A).
The global crude death rates of PD for the years 2000, 2010 and 2019 showed an increasing trend for both men and women. Increasing numbers were also seen in CRC and PC (Fig. 1B), but mortality of EC and SC decreased. For LC, a strong reduction was documented from 2000 to 2010, followed by a slight increase until the year 2019 ( Fig. 1B).

DISCUSSION
In the present study, we observed that PD-specific mortality was inversely correlated with the mortality of CRC and PC; even countries with high PD mortality were associated with the lower mortality of CRC and PC. These findings are for the most part consistent with previous reports including a nationwide population-based cohort study describing that PD patients had a decreased risk of SC, CRC, LC as well as PC [13]. However, and a little unexpected, a positive association between PD and LC was revealed in this study. In detail, this positive association with PD was mostly seen in the two virusassociated pathogenetic subtypes: LC_hB and LC_hC.
An Israeli study from 2019 also described that hepatitis B viruses (HBV) and hepatitis C viruses (HCV) were risk factors for PD development [14], while a large Taiwanese cohort study concluded that HCV-positive, but not HBV-infected patients have an enhanced risk of developing PD [15]. Mechanistically, HCV has been shown to cause the loss of dopaminergic neurons by inducing neuro-inflammation [16]. Taking into account the even stronger correlation, we observed between HBV and PD, it seems reasonable to suggest that HBV is also a likely co-risk factor for PD development. In addition to neuro-inflammation, neuronal cell damage and cell death could be induced directly by viral replication or indirectly by activating further innate immune response mechanisms [17].
LC_alcohol tended to be weakly associated inversely with PD. This can be interpreted as supporting an old hypothesis stating that moderate alcohol consumption might be protective for PD; which might be attributable, for example, to the urate-elevating effects of beer [18].
In addition, likely explanations for the decrease in correlation intensity are improvements in therapeutical management of PD, especially in the developed countries, combined with a strong increase of GI cancer numbers in developing countries [1,19].
We found no significant correlation between EC and PD. This might be due to the incapability to subdivide EC into the two main subtypes of esophageal squamous cell carcinoma and adenocarcinoma, since the Global Health Observatory database does not provide this classification.
Despite this clear limitation of the present study, this is the first report correlating PD and GI cancers mortalities on the global scale. In sum, our data are in favor of the hypothesis of opposing biological processes driving the two types of diseases. As we mentioned before, the neurodegenerative disease gradually leads to the death of neurons, while cancer is characterized by ceaseless cell proliferation [9].
Given the biologically opposing disease mechanisms, future research must address the "chicken or egg" causality dilemma of PD's correlation with most GI cancers. Albeit successful HBV vaccination plus the dramatically improved clinical management of HCVinfected patients reduced the number of novel virusassociated LC cases, the positive correlation of the latter with PD warrants detailed analysis. Basing on these data, it is only logical to conclude, that viral hepatitis prevention thus might, on the longer run, help reduce the number of people affected by PD.
Finally, both lines of future research aiming at unraveling the functional biological link between neurodegeneration, viral infection and tumor development hold great potential for developing novel therapeutic concepts.